Globally nearly 7 million people suffer from consequences of spinal cord injury. Many years of research using animal models lead to the development of current spinal cord injury (SCI) rehabilitation methods, including the epidural spinal cord (ES) stimulation. ES stimulation has been shown to evoke rhythmic locomotor activity in rats, cats and humans, including humans with clinically complete SCI. However, the evoked rhythmic motor patterns do not permit full weight support and often demonstrate non-physiological co-activation of antagonists, atypical locomotor kinematics and muscle synergies, i.e. groups of muscles activated together and producing basic activity patterns that reflect the modular organization of the locomotor control system. Further progress of the promising ES therapies requires a thorough understanding of the mechanisms underlying generation of distinct kinematic and muscle synergies during walking activated by ES of the spinal cord. The overall goal of this project is to determine the contribution of motion-dependent afferent pathways, selected ascending and descending pathways in the spinocerebellar loop, and the central pattern generator (CPG) circuitry to the generation of the distinct kinematic and muscle synergies during normal walking and ES-activated walking in cats with intact and partially transected spinal cord. This goal will be accomplished in experimental and neuromechanical computational studies performed in close collaboration among 4 research groups (Georgia Institute of Technology; Karolinska Institute, Sweden; Drexel University and Pavlov Institute of Physiology, Russia). In Aim 1 we will determine kinematic and muscle synergies during forward walking in the decerebrate cat whose locomotion is activated by ES or by commands from the brain (stimulation of the mesencephalic locomotor region, MLR), and compare them with the synergies generated by a neuromechanical model of hindlimb locomotion. In Aim 2 we will determine characteristics of activity patterns of individual spinal interneurons in the lumbosacral enlargement during MLR-evoked and ES-evoked walking in the decerebrate cat and use the neuromechanical computational model to reproduce and explain the recorded patterns and their differences. In Aim 3 we will determine characteristics of activity patterns of neurons in selected ascending and descending pathways in the spinocerebellar loop during MLR- and ES-evoked locomotion and investigate their effects on locomotor kinematic and muscle synergies in a neuromechanical model of hindlimb locomotion. Aim 4 will determine effects of opening the spinocerebellar loop using a reversible dorsal hemisection of the spinal cord (rDHS, produced by cooling the dorsal half of spinal pathways at the low thoracic level) on kinematic and muscle synergies, as well as on characteristics of activity patterns of the same individual spinal interneurons during MLR-evoked and ES-evoked walking. We anticipate that this study will improve our understanding of how ES, sensory and supraspinal inputs, and CPG contribute to kinematic and muscle synergies during locomotion and thus will provide scientific basis for improvement of ES- stimulation therapies.